Cysteine derivatives

ABSTRACT

Objects of the present invention are to provide an oxidative stress inhibitor which is capable of suppressing the expression of a cytotoxic protein and the activation of a gene transcriptional regulatory factor taking part such expression of a cytotoxic protein and exhibits good feeling upon use and safety; to provide a method for preventing, retarding, alleviating or treating a skin change due to aging or an undesirable aesthetic skin change, both caused or promoted by an oxidative stress; and to provide a cosmetic composition or dermatologic preparation for external use comprising the oxidative stress inhibitor as an effective ingredient, and for those purposes are employed an oxidative stress inhibiting agent which comprises, as an effective ingredient, at least one selected from cysteine or cystine derivatives and the salts thereof.

This application is a 371 of PCT/JP99/05584, filed on Oct. 8, 1999.

TECHNICAL FIELD

The present invention relates to an oxidative stress inhibitor usefulfor prevention, retardation, alleviation or treatment of diseases ordermal injuries or diseases caused by an oxidative stress; a method forinhibiting an oxidative stress by using such an oxidative stressinhibitor; and a cosmetic composition or dermatologic preparation forexternal use which comprises such an oxidative stress inhibitor as aneffective ingredient.

BACKGROUND ART

In recent years, causes of diseases or dermal injuries or diseasesbrought about by an oxidative stress such as ultraviolet rays, activeoxygen, free radicals or the like have been searched briskly. Forexample, it is known that cytotoxic cytokines such as IL-1α, TNF-α andthe like or extracellular matrix proteases such as collagenase and thelike are closely related to aging, canceration or malignant alteration,edema, pigmentation or the like as its cause (for example, “OxidativeStress in Dermatology”, Marcel Dekker, Inc., pp. 187-205, 1993).Expression of a gene coding for such a protein is mainly controlled atthe level of genetic transcription, whereas, regarding cytotoxicproteins such as cytotoxic cytokines and extracellular matrix proteases,it is controlled by a transcriptional regulatory factor such as NF-κB orAP-1 (for example, “Active oxygen and Signal transmission”, KodanshaScientific, pp. 37-46, 1996). In practice, NF-κB and AP-1 are known tobe activated by an oxidative stress and promote the expression ofcytotoxic protein (for example, “Active oxygen and Signal transmission”,Kodansha Scientific, pp. 1-20, 1996). Diseases or dermal injuries ordiseases caused by an oxidative stress are therefore expected to beprevented, retarded, alleviated or treated if it becomes possible tosuppress the activation of NF-κB or AP-1 due to an oxidative stress.

There is a description that the activation of NF-κB is inhibited by asulfur-containing antioxidant such as N-acetyl-L-cysteine or pyrrolidinedithiocarbamate (for example, “Active oxygen and Signal transmission”,Kodansha Scientific, pp. 37-46, 1996). It is reported thatN-acetyl-L-cysteine can also suppress the activation of AP-1 (forexample, “FEBS Letters”, Vol. 384, pp. 92-96, 1996). These compoundsare, however, accompanied with such drawbacks as insufficient effects orstrong cytotoxicity. Sulfur-containing compounds such asN,N′-diacetyl-L-cystine are known to suppress dermal inflahmmationinduced by leukotrienes (ex. U.S. Pat. No. 4,827,016), but not known toinhibit cytokines or transcription factor taking part in aging,canceration, edema, pigmentation or the like. In addition tosulfur-containing antioxidants, there are reports on retinoic acid usedfor inhibiting the activation of AP-1 and the expression ofextracellular matrix proteases (for example, “Nature”, Vol. 379, pp.335-339, 1996); and steroidal anti-inflammatory drugs or non-steroidalanti-inflammatory drugs used for suppressing the activation of NF-κB(for example, “Bio Essays”, Vol. 18, pp. 373-378, 1996). Retinoic acidand steroidal anti-inflammatory drugs are not free from side effectssuch as detachment of the skin and steroid-induced skin diseases,respectively, so that they cannot be used freely. Non-steroidalanti-inflammatory drugs do not cause systemic side effects which areobserved upon use of a steroidal anti-inflammatory drug, but there isroom for improvement in its local side effects. In addition, its effectsfor suppressing the activation of inflammatory factors are insufficient.

As one of the diseases or dermal injuries or diseases caused by anoxidative stress, a change in the skin due to aging or an undesirableesthetic change in the skin can be mentioned. It is reported that inorder to prevent or retard such a change, a natural extract havingaction for alleviating skin roughness or the component containedtherein, such as astaxantin, and a cystine derivative are in combinationapplied to the skin (for example, Japanese Patent Application Laid-Open:(Kokai) No. Hei 9-143,063). According to the report, such a combinationcontributes to the recovery of resilience or luster of the skin or theamelioration of the somber coloring,-but does not exhibit sufficienteffects. In addition, its effects against skin wrinkles or flabby skin,the most eminent symptoms in the observation of the aged skin, are,however, not revealed.

Induction or promotion of skin wrinkles or flabby skin is a typicalexample of skin change due to aging or an undesirable aesthetic skinchange, both brought about by an oxidative stress. The sun light orultraviolet rays therefrom can be mentioned as its cause (for example,“Shin Keshohin-gaku”, Nanzando, pp. 38-46, 1993). As a method forpreventing or retarding such a change, application of an antioxidantsuch as tocopherol, ascorbic acid, N-acetyl-L-cysteine or the like tothe kin is reported (for example, “Photodermatol. Photoimmunol.Photomed., Vol.7, pp. 56-62, 1990 or Japanese Language Laid-OpenPublication (PCT) No. Hei 6-510,542). Prevention or retardation is alsoeffected by the application of an anti-inflammatory drug or anultraviolet absorber, other than an antioxidant (for example,“Photodermatol. Photoimmunol. Photomed., Vol.7, pp. 153-158, 1990 or J.Photochem. Photobiol. B: Biol., Vol. 9, pp. 323-334, 1991) orimprovement is conducted using retinoic acid (for example, “J. Invest.Dermatol., Vol. 98, pp. 248-254, 1992). These compounds are, however,accompanied with the problems such as insufficient effects, strongcytotoxicity and low light stability. Moreover, anti-inflammatory drugsand retinoic acid are not free from side effects as described above.

DISCLOSURE OF THE INVENTION

Objects of the present invention are to provide, based on theabove-described background art, an oxidative stress inhibitor which iscapable of suppressing the activation of a gene transcriptionalregulatory factor taking part in the expression of a cytotoxic proteinand exhibits good feeling upon use and safety; to provide a method forpreventing, retarding, alleviating or treating a skin change due toaging or an undesirable aesthetic skin change, both caused or promotedby an oxidative stress; and to provide a cosmetic composition ordermatologic preparation for external use comprising the oxidativestress inhibitor as an effective ingredient.

The present inventors have proceeded with an extensive investigationwith a view toward attaining the above-described objects. As a result,they have found that the above-described objects can be attained byusing a cysteine or cystine derivative represented by thebelow-described general formula (I), (II) or (III) or a salt thereof asan effective ingredient; or by using a cysteine or cystine derivativerepresented by the below-described general formula (IV) or a saltthereof and an antioxidant, anti-inflammatory drug or ultravioletabsorber in combination. Based on these findings, the present inventionhas been completed.

Accordingly, the present invention relates to an oxidative stressinhibitor which comprises as an effective ingredient at least oneselected from the cysteine or cystine derivatives represented by thebelow-described general formula (I) and the salts thereof.

In the above-described general formula (I), R¹ represents a hydrogenatom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, analkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; the two E's represent, each independently, a hydrogenatom or an alkyl group having 1-6 carbon atoms, and g stands for aninteger of 0 to 5, while R² represents a hydrogen atom, an alkyl grouphaving 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atomsor a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms. R³ represents a hydrogen atom, an aminocarbonyl group, an acylgroup having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms,a hydroxyalkyl group having 1-22 carbon atoms, a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atomor a group represented by the following general formula (1).

In the above-described general formula (1), R⁴ represents a hydrogenatom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, analkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; the two F's represent, each independently, a hydrogenatom or an alkyl group having 1-6 carbon atoms, and h stands for aninteger of 0 to 5, while R⁵ represents a hydrogen atom, an alkyl grouphaving 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atomsor a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.

The cysteine or cystine derivatives represented by the above-describedgeneral formula (I) are not known in the literature, and therefore, arenew compounds. Accordingly, the present invention relates also to thecysteine or cystine derivatives represented by the above-describedgeneral formula (I) and the salts thereof per se.

The present invention relates also to an oxidative stress inhibitorwhich comprises as an effective ingredient at least one selected fromthe cystine derivatives represented by the below-described generalformula (II) and the salts thereof.

In the above-described general formula (II), R⁶ and R⁸ represent ahydrogen atom, an aminocarbonyl group, an acyl. group having 2-22carbon-atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms; the two T's and the two V'srepresent, each independently, a hydrogen atom or an alkyl group having1-6 carbon atoms, and i and j stand, each independently, for an integerof 0 to 5, while R⁷ and R⁹ represent a hydrogen atom, an alkyl grouphaving 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atomsor a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁶ and R⁸ represent a hydrogen atom oran acyl group having 2 carbon atoms, and i and j are each 1, R⁷ and R⁹represent an alkyl group having 2-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms.

Also, the present invention relates to a preventing and/or treatingagent for oxidative stress-induced diseases, inter alia, ultravioletrays-induced diseases, which agent comprises at least one selected fromthe cysteine or cystine derivatives represented by the above-describedgeneral formula (I) or (II) and the salts thereof.

Furthermore, the present invention relates to a cosmetic additive to beadded as a component to a cosmetic composition, which additive consistsof at least one selected from the cysteine or cystine derivativesrepresented by the above-described general formula (I) or (II) and thesalts thereof.

Still furthermore, the present invention relates to a cosmeticcomposition or a dermatologic preparation for external use whichcomprises at least one selected from the cysteine or cystine derivativesrepresented by the above-described general formula (I) or (II) and thesalts thereof. The cosmetic composition of the present invention isuseful for preventing or alleviationg oxidative stress-induced dermalinjuries, and the dermatologic preparation for external use of thepresent invention is useful for preventing or treating oxidativestress-induced diseases.

Furthermore, the present invention relates to a method for preventing,retarding, alleviating or treating a skin change due to aging or anundesirable aesthetic skin change, both caused or promoted by anoxidative stress, which method comprises applying onto the skin acosmetic composition or a dermatologic preparation for external usecomprising, as an effective ingredient, at least one selected from thecysteine or cystine derivatives represented by the above-describedgeneral formula (I) or the below-described general formula (III) and thesalts thereof.

In the above-described general formula (III), R¹⁰ and R¹² represent ahydrogen atom, an aminocarbonyl group, an acyl group having 2-22 carbonatoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms; the two W's and the two X'srepresent, each independently, a hydrogen atom or an alkyl group having1-6 carbon atoms, and k and 1 stand, each independently, for an integerof 0 to 5, while R¹¹and R¹³ represent a hydrogen atom, an alkyl grouphaving 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atomsor a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹⁰ and R¹² represent a hydrogen atomor an acyl group having 2 carbon atoms, and k and l are each 1, R¹¹ andR¹³ represent an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms.

Moreover, the present invention relates to a cosmetic composition or adermatologic preparation for external use which comprises Component (A)and Component (B), each described below.

Component (A): At least one selected from the cysteine or cystinederivatives represented by the below-described general formula (IV) andthe salts thereof.

In the above-described general formula (IV), R⁴ represents a hydrogenatom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, analkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; the two Y's represent, each independently, a hydrogenatom or an alkyl group having 1-6 carbon atoms, and m stands for aninteger of 0 to 5, while A represents—O— or —NH—, R¹⁵ represents ahydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atom or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms, and R¹⁶ represents a hydrogen atom,an aminocarbonyl group an acyl group having 2-22 carbon atoms, an alkylgroup having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbonatoms, a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22carbon atoms, or a group represented by the below-described generalformula (2), with the proviso that when R¹⁴ represents a hydrogen atomor when R¹⁴ represents an aminocarbonyl group or an acyl group having 2carbon atoms and A represents —O—, R¹⁵ represents an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.

In the above-described general formula (2), R¹⁷ represents a hydrogenatom, an aminocarbonyl group, an acyl group having 2-22 carbon atoms, analkyl group having 1-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; the two Z's represent, each independently, a hydrogenatom or an alkyl group having 1-6 carbon atoms, and n stands for aninteger of 0 to 5, while B represents —O— or —NH—, and R¹⁸ represents ahydrogen atom, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms, with the proviso that when R¹⁷represents a hydrogen atom or when R¹⁷ represents an aminocarbonyl groupor an acyl group having 2 carbon atoms and B represents —O—, R¹⁸represents an alkyl group having 1-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms.

Component (B): At least one selected from an anti-oxidant,anti-inflammatory drug and ultraviolet absorbor.

Hereinbelow will be described the present invention in greater detail.

First, specific examples of the compounds relating to the presentinvention will be described.

In the cysteine or cystine derivative represented by the above-describedgeneral formula (I), (II), (III) or (IV), or the salts thereof, as R¹,R⁴, R⁶, R⁸, R¹⁰, R¹², R¹⁴ and R¹⁷, there may be mentioned hydrogen atomand aminocarbonyl, acetyl, propionyl, isopropionyl, n-butyryl,isobutyryl, sec-butyryl, tert-butyryl, n-valeryl, sec-valeryl, pivaloyl,isovaleryl, n-hexanoyl, cyclohexanoyl, n-heptanoyl, n-octanoyl,2-ethylhexanoyl, nonanoyl, isononanoyl, decanoyl, isodecanoyl,undecanoyl, lauroyl, tridecanoyl, isotridecanoyl, myristoyl, palmitoyl,isopalmitoyl, stearoyl, isostearoyl, oleoyl, docosanoyl, methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-amyl,sec-amyl, tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl, n-octyl,2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl, lauryl,tridecyl, isotridecyl, myristyl, cetyl, isocetyl, stearyl, isostearyl,oleyl, behenyl, 2-hydroxyethyl, 2-hydroxypropyl, 2-hydroxyisopropyl,2-hydroxy-n-butyl, 2-hydroxyisobutyl, 2-hydroxy-sec-butyl,2-hydroxy-tert-butyl, 2-hydroxy-n-amyl, 2-hydroxy-sec-amyl,2-hydroxy-tert-amyl, 2-hydroxyisoamyl, 2-hydroxy-n-hexyl,2-hydroxycyclohexyl, 2-hydroxy-n-heptyl, 2-hydroxy-n-octyl,2-hydroxy-2-ethylhexyl, 2-hydroxynonyl, 2-hydroxyisononyl,2-hydroxydecyl, 2-hydroxyisodecyl, 2-hydroxyundecyl, 2-hydroxylauryl,2-hydroxytridecyl, 2-hydroxyisotridecyl, 2-hydroxymyristyl,2-hydroxycetyl, 2-hydroxyisocetyl, 2-hydroxystearyl,2-hydroxyisostearyl, 2-hydroxyoleyl, 2-hydroxybehenyl,3-methoxy-2-hydroxypropyl, 3-ethoxy-2-hydroxypropyl,3-propoxy-2-hydroxypropyl, 2-isopropoxy-2-hydroxypropyl,3-n-butoxy-2-hydroxypropyl, 3-isobutoxy-2-hydroxypropyl,3-sec-butoxy-2-hydroxypropyl, 3-tert-butoxy-2-hydroxypropyl,3-n-amyloxy-2-hydroxypropyl, 3-sec-amyloxy-2-hydroxypropyl,3-tert-amyloxy-2-hydroxypropyl, 3-isoamyloxy-2-hydroxypropyl,3-n-hexyloxy-2-hydroxypropyl, 3-cyclohexyloxy-2-hydroxypropyl,3-n-heptyloxy-2-hydroxypropyl, 3-n-octyloxy-2-hydroxypropyl,3-(2-ethylhexyl)oxy-2-hydroxypropyl, 3-nonyloxy-2-hydroxypropyl,3-isononyloxy-2-hydroxypropyl, 3-decyloxy-2-hydroxypropyl,3-isodecyloxy-2-hydroxypropyl, 3-undecyloxy-2-hydroxypropyl,3-lauryloxy-2-hydroxypropyl, 3-tridecyloxy-2-hydroxypropyl,3-isotridecyloxy-2-hydroxypropyl, 3-myristyloxy-2-hydroxypropyl,3-cetyloxy-2-hydroxypropyl, 3-isocetyloxy-2-hydroxypropyl,3-stearyloxy-2-hydroxypropyl, 3-isostearyloxy-2-hydroxypropyl,3-oleyloxy-2-hydroxypropyl, 3-behenyloxy-2-hydroxypropyl and the likegroups.

As R², R⁵, R⁷, R⁹, R¹¹, R¹³, R¹⁵ and R¹⁸, there may be mentionedhydrogen atom and methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-amyl, sec-amyli tert-amyl, isoamyl, n-hexyl,cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl,isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, cetyl,isocetyl, stearyl, isostearyl, oleyl, behenyl, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxyisopropyl, 2-hydroxy-n-butyl,2-hydroxyisobutyl, 2-hydroxy-sec-butyl, 2-hydroxy-tert-butyl,2-hydroxy-n-amyl, 2-hydroxy-sec-amyl, 2-hydroxy-tert-amyl,2-hydroxyisoamyl, 2-hydroxy-n-hexyl, 2-hydroxycyclohexyl,2-hydroxy-n-heptyl, 2-hydroxy-n-octyl, 2-hydroxy-2-ethylhexyl,2-hydroxynonyl, 2-hydroxyisononyl, 2-hydroxydecyl, 2-hydroxyisodecyl,2-hydroxyundecyl, 2-hydroxylauryl, 2-hydroxytridecyl,2-hydroxyi-sotridecyl, 2-hydroxymyristyl, 2-hydroxycetyl,2-hydroxyisocetyl, 2-hydroxystearyl, 2-hydroxyisostearyl,2-hydroxyoleyl, 2-hydroxybehenyl, 2-methoxy-2-hydroxypropyl,2-ethoxy-2-hydroxypropyl, 3-propoxy-2-hydroxypropyl,2-isopropoxy-2-hydroxypropyl, 3-n-butoxy-2-hydroxypropyl,3-isobutoxy-2-hydroxypropyl, 3-sec-butoxy-2-hydroxypropyl,3-tert-butoxy-2-hydroxypropyl, 3-n-amyloxy-2-hydroxypropyl,3-sec-amyloxy-2-hydroxypropyl, 3-tert-amyloxy-2-hydroxypropyl,3-isoamyloxy-2-hydroxypropyl, 3-n-hexyloxy-2-hydroxypropyl,3-cyclohexyloxy-2-hydroxypropyl, 3-n-heptyloxy-2-hydroxypropyl,3-n-octyloxy-2-hydroxypropyl, 3-(2-ethylhexyl)oxy-2-hydroxypropyl,3-nonyloxy-2-hydroxypropyl, 3-isononyloxy-2-hydroxypropyl,3-decyloxy-2-hydroxypropyl, 3-isodecyloxy-2-hydroxypropyl,3-undecyloxy-2-hydroxypropyl, 3-lauryloxy-2-hydroxypropyl,3-tridecyloxy-2-hydroxypropyl, 3-isotridecyloxy-2-hydroxypropyl,3-myristyloxy-2-hydroxypropyl, 3-cetyloxy-2-hydroxypropyl,3-3-isocetyloxy-2-hydroxypropyl, 3-stearyloxy-2-hydroxypropyl,3-isostearyloxy-2-hydroxypropyl, 3-oleyloxy-2-hydroxypropyl,3-behenyloxy-2-hydroxypropyl and the like groups.

The cysteine or cystine derivatives represented by the above-describedgeneral formula (I), (II), (III) or (IV) may be either in the opticallyactive form or racemic form. Among them, L and DL forms are preferred.As the salts of the compound represented by the above-described generalformula (I), (II), (III) or (IV), there may be mentionedhydrohalogenides such as hydrochloride, hydrobromide, hydroiodide andthe like; salts of an inorganic acid such as sulfate, carbonate,phosphate and the like; and salts of an organic acid such as acetate,tartrate, citrate, p-toluenesulfonate, glycolate, malate, lactate, fattyacid salt, acidic amino acid salts, pyrroglutamate and the like. Thesesalts may be used either singly or in combination.

Next will be made a description of a process for producing the compoundsof the present invention.

The cysteine or cystine derivative represented by the above-describedgeneral formula (I), (II), (III) or (IV) can be led to its amide orester from by reacting, for example, L- or DL-cysteine or L- orDL-cystine with an acid anhydride, acid chloride, alkyl halide, epoxyalkane or alkyl glycidyl ether, whereby the amino group is acylated,alkylated, hydroxyalkylated or 3-alkoxy-2-hydroxypropylated, and thensubjecting the resulting compound to dehydration-condensation with analkyl amine or an alcohol.

The cysteine or cystine derivative represented by the above-describedgeneral formula (I) or (IV) can be produced, for example, by reacting L-or DL-cysteine amide or L- or DL-cystine diamide with an acid anhydride,acid chloride, alkyl halide, epoxy alkane or alkyl glycidyl ether,whereby the amino group is acylated, alkylated, hydroxyalkylated or3-alkoxy-2-hydroxypropylated.

The cysteine or cystine derivative represented by the above-describedgeneral formula (II), (III) or (IV) can be produced, for example, byreacting L- or DL-cysteine ester or L- or DL-cystine diester with anacid anhydride, acid chloride, alkyl halide, epoxy alkane or alkylglycidyl ether, whereby the amino group is acylated, alkylated,hydroxyalkylated or 3-alkoxy-2-hydroxypropylated.

In the next place, the above-described Component (B) to be used, incombination with the compound of the present invention, for preparingthe cosmetic composition or dermatologic preparation for external useaccording to the present invention.

As the antioxidant as Component (B), there may be mentioned ascorbicacid, sodium ascorbate, ascorbyl stearate, ascorbyl palmitate, ascorbyldipalmitate, magnesium ascorbate phosphate, α-tocopherol, β-tocopherol,γ-tocopherol, δ-tocopherol, α-tocotrienol, β-tocotrienol, γ-tocotrienol,δ-tocotrienol, tocopherol acetate, natural vitamin E, tocopherolnicotinate, Trolox, N-acetylcysteine, α-lipoic acid, dehydrolipoic acid,glutathione, uric acid, dihydroxytoluene, butylhydroxyanisole,dibutylhydroxytoluene, erysorbic acid, sodium erysorbate, gallic acid,propyl gallate, tannic acid, catechin, caffeic acid, ferulic acid,protocatechuic acid, oryzanol, quercetin, epigallocatechin gallate,carnosol, sesamol, sesamine, sesamolin, zingerone, Shogaol, capsaicin,vanillyl amide, ellagic acid, bromophenol, flavoglacin, melanoidine,retinol, dehydroretinol, vitamin A oil, retinol acetate, retinolpalmitate, retinal, retinoic acid, riboflavin, riboflavin butyrateester, flavin mononucleotide, flavin adenine dinucleotide, superoxidedismutase, ubiquinol, ubiquinone, catalase, glutathione peroxidase,catalase ferroxidase, metallothionein, ceruloplasmin, transferrin,lactoferrin, albumin, bilirubin, citric acid, tartaric acid, malic acid,phytic acid, histidine, tryptophan, O-phosphono-pyridoxylidenerhodamine, N-(2-hydroxybenzyl)amino acid as described in U.S. Pat. No.5,594,012, N-(4-pyridoxylmethylene)amino acid and the like.

As the anti-inflammatory drug as Component (B), there may be mentionedglycyrrhetinic acid, glyceryl glycyrrhetinate, stearyl glycyrrhetinate,glycyrrhetinyl stearate, glycyrrhizic acid, methyl glycyrrhizinate,dipotassium glycyrrhizinate, salicylic acid, sodium salicylate,resorcin, guaiazulene, allantoin, lithospermum root extract, shikonin,diphenhydramine hydrochloride, chlorpheniramine maleate, ichthammol,γ-oryzanol, thianthol, sodium copper chlorophyllin, ibuprofen,indomethacin, tranexamic acid, hydrocortisone and the like.

As the ultraviolet absorber as Component (B), there may be mentioned2-hydroxy-4-methoxybenzophenone (oxybenzone),2-hydroxy-4-methoxybenzophenone-5-sulfonic acid, sodium2-hydroxy-4-methoxybenzophenone-5-sulfonate,dihydroxydimethoxybenzophenone, sodiumdihydroxydimethoxybenzophenonesulfonate, 2,4-dihydroxybenzophenone,tetrahydroxybenzophenone, p-aminobenzoic acid, sodium p-aminobenzoate,ethyl p-aminobenzoate, glyceryl p-aminobenzoate, amylp-dimethylaminobenzoate, 2-ethylhexyl p-dimethylaminobenzoate, ethylp-methoxycinnamate, isopropyl p-methoxycinnamate, 2-ethylhexylp-methoxycinnamate (cinnoxate), 2-ethoxyethyl p-methoxycinnamate, sodiump-methoxycinnamate, potassium p-methoxycinnamate, glyceryldi(p-methoxycinnamic acid)mono-2-ethylhexanoate, methyldiisopropylcinnamate, 2-ethylhexyl salicylate, phenyl salicylate,homomenthyl salicylate, dipropylene glycol salicylate, ethylene glycolsalicylate, myristyl salicylate, methyl salicylate,4-tert-butyl-4′-methoxydibenzoylmethane,2-(2′-hydroxy-5′-methylphenyl)benzotriazole, methyl anthranilate, ethylanthranilate, urocanic acid, ethyl urbcanate,2,4,6-tris[4-(2-ethylhexyloxycarbonyl)anilino]-1,3,5-triazine, titaniumoxide,3,3′-(1,4-phenylenedimethylidene)bis(7,7-dimethyl-2-oxo-bicyclo[2.2.1]heptane-1-methanesulfonicacid) (Mexoryl SX), and the like.

Next will be made a description of the way of administering theoxidative stress inhibitor of the present invention.

The oxidative stress inhibitor of the present invention represented bythe above-described general formula (I) or (II) can be administeredorally or parenterally, but direct administration to an oxidative stressactivating system is preferred. Usually, preferred is the use thereof inthe form where it is incorporated in a cosmetic composition ordermatologic preparation for external use. In the method of the presentinvention for preventing, retarding, alleviating or treating a dermalchange induced by an oxidative stress or wrinkles or flabbiness of theskin induced by light, preferred is direct administration of a cosmeticcomposition or dermatologic preparation for external use containing thecompound of the above-described general formula (III) to the healthyskin or to any site wherein a dermal change or formation of wrinkles orflabbiness has advanced or is advancing.

When the compound represented by the above-described general formula(I), (II) or (III), or the above-described Components (A) and (B) areincorporated in a cosmetic composition as an effective ingredient forprevention or alleviation of skin injuries caused by an oxidativestress, it can be added in an amount of 0.01 to 10 wt. %, preferably 0.1to 5 wt. %. When the compound represented by the above-described generalformula (I), (II) or (III) or the above-described Components (A) and (B)are incorporated in a dermatologic preparation for external use as aneffective ingredient for prevention or treatment of diseases inducedfrom an oxidative stress, it can be added in an amount of 0.01 to 50 wt.%, preferably 0.1 to 20 wt. %. When the amount is less than 0.01 wt. %,the resulting preparation cannot fully exhibit oxidative stressinhibiting function, while when the amount exceeds 50 wt. %, on theother hand, it involves problems in feeling upon use such as creakyfeeling onto the skin, and the like. Therefore, amounts outside theabove range are not preferred.

It is preferred to continuously apply, to the skin, the cosmeticcomposition or dermatologic preparation for external use containing thecompound represented by the above-described general formula (I), (II) or(III) or the above-described Components (A) and (B) for a long period oftime, more specifically, for at least one month. It is more preferredthat for the prevention of skin injuries or rag diseases caused by anoxidative stress, the preparation is continuously applied for a periodnot less than 3 months to the death of the patient, while for thealleviation or treatment of the skin injuries or diseases caused by anoxidative stress, it is applied for a period not less than 3 months to10 years.

Application frequency preferably ranges from once/week to 5 times/day,with once/day to three times/day being more preferred. The amount of thecompound represented by the above-described general formula (I), (II) or(III), or the above-described Components (A) and (B) to be appliedpreferably ranges from 0.003 μg/cm² to 200 mg/cm², with 1 μg/cm² to 50mg/cm² being more preferred.

When the compound represented by the above-described general formula(I), (II) or (III), or the above-described Components (A) and (B) areincorporated in a cosmetic composition or a dermatologic preparation forexternal use, components ordinarily employed for a cosmetic compositionor dermatologic preparation for external use can be, in addition to theoxidative stress inhibitor of the present invention, added within anextent not damaging the advantages of the present invention.

As such components ordinarily employed for a cosmetic composition or adermatologic preparation for external use, there may be mentioned oilyraw materials, surfactants, solvents, humectants, high-molecular weightsubstances, powdery substances, colorants, perfumes, percutaneousabsorption promoters, components derived from animals or plants, and thelike.

As the oily raw material, there may be mentioned oils and fats such asanimal and vegetable oils, waxes such as lanolin, hydrocarbons such asparaffin, higher alcohols such as cetanol, higher fatty acids such asstearic acid, sterols, phospholipids such as lecithin, synthetic esterssuch as myristic acid, metal soaps, silicone oils and the like.

As the surfactant, there may be mentioned anionic surfactants, cationicsurfactants, amphoteric surfactants, nonionic surfactants, emulsifiers,solubilizing agents, and the like.

As the solvent, there may be mentioned lower alcohols such as ethanol,ethers, glycerins, liquid nonionic surfactants, liquid oily rawmaterials, other organic solvents, water, and the like.

As the humectant, there may be mentioned polyhydric alcohols such asglycerin, salts of an organic acid such as pyrrolidonecarboxylic acid,urea, mucopolysaccharides such as hyaluronic acid, salts of an aminoacid such as proline, and the like.

As the high molecular weight substance, there may be mentioned naturalhigh molecular weight compounds such as collagen, semi-synthetic highmolecular weight compounds such as partially deacetylated chitin,synthetic high molecular weight compounds such as carboxymethylcellulose, and the like.

As the powdery substance, there may be mentioned inorganic pigments suchas talc, functional pigments such as synthetic mica, hybrid fine powder,pearl-lustrous pigments such as titanium-dioxide coated mica,photochromic pigments, high molecular powders such as nylon powder,organic powders such as N^(ε)-lauroyl lysine, and the like.

As the colorant, there may be mentioned legal 1st-class tar pigments,legal 2nd-class tar pigments, legal 3rd-class tar pigments, hair dyes,natural colorants, mineral colorants, and the like.

As the perfume, there may be mentioned animal perfumes such as musk,plant perfumes such as jasmine oil, synthetic perfumes such asα-amylcinnamaldehyde, mixed perfumes, and the like.

As percutaneous absorption promoters, there may be mentioned urea,2-pyrrolidone, 1-hexanol, 1-octanol, 1-decanol, 1-menthol, sodium laurylsulfate, isopropyl myristate, n-hexyl acetate, oleic acid, and the like.

As the components derived from animals or plants, there may be mentionedlicorice extract, placenta extract, aqueous hamamelis, and the like.

No particular limitations are imposed on the dosage form of the cosmeticcomposition or dermatologic preparation for external use containing theabove-described general formula (I), (II) or (III) or theabove-described Components (A) and (B), and any dosage form such assolution, paste, gel, solid or powder can be adopted. The cosmeticcomposition or dermatologic preparation for external use according tothe present invention can be used as or for oil, lotion, cream, milkylotion, gel, shampoo, hair rinse, hair conditioner, enamel, foundation,lipstick, face powder, pack, ointment, tablet, injection, granule,capsule, perfume, powder, eau de Cologne, dental paste, soap, aerosol,cleansing foam and the like; and also as or for skin aging preventive oralleviative, skin inflammation preventive or alleviative, bath agent,hair tonic, skin vitalizing lotion, sunburn preventive, preventive oralleviative of photosensitivity such as xeroderma pigmentosum or solarurticaria, preventive or alleviative of photoallergy, preventive oralleviative of optical immunosuppression, preventive or alleviative ofrough skin caused by injury, chaps, cleft or the like, and the like. Itcan be used as or for a preventive and/or curative for various diseasesinduced by the activation of an oxidative stress, e.g., rheumaticdiseases such as rheumatoid arthritis and the like, arthritis, skindiseases such as atopic dermatitis, contact dermatitis, psoriasisvulgaris and the like, respiratory diseases such as bronchial asthma,bronchitis and the like, inflammatory bowel diseases, acute or chronichepatitis, acute or chronic nephritis, Mediterranean fever, ischemicdiseases such as myocardial infarction, and the like.

To the cosmetic composition or dermatologic preparation for external usecontaining the compound represented by the above-described generalformula (I), (II) or (III) or the above-described Components (A) and(B), other ordinarily employed components in cosmetic compositions ordermatologic preparations for external use a can be added within anextent not impairing the advantages of the present invention. As suchother ordinarily employed components in cosmetic compositions ordermatologic preparations for external use, there may be mentionedantiseptic bactericides, antioxidants, chelating agents, discolorationpreventives, buffers, medicaments for acne vulgaris, antidandruffs orantipruritics, antiperspirants or antibromics, antipyrotics, acaricidesor pediculicides, keratin softeners, medicaments for xeroderma,virucides, hormones, vitamins, amino acids, peptides, proteins,astringents, coolants, melanin synthesis inhibitors (whitening agents),antibiotics, antimycotics, hair growth promoters and the like.

Best Mode for Carrying out the Invention

The present invention will be hereinafter described in greater detailwith reference to Examples (Synthesis Examples, Test Examples andFormulation Examples). It should however be borne in mind that thepresent invention is not limited to or by these Examples. In theseExamples, the amount of each component is indicated by wt. %.

First, Synthesis Examples will be described.

SYNTHESIS EXAMPLE 1 Synthesis of Cystine Diamide Derivatives

To 7 ml of acetonitrile were added successively 0.15 g of L-cystinediamide dihydrochloride, 0.21 g of n-hexanoic anhydride and 0.10 g oftriethylamine, followed by stirring overnight at room temperature. Thereaction mixture was concentrated, and the crude crystals thus obtainedwere purified by high-performance liquid chromatography (HPLC separationwith an apparatus for high-performance liquid chromatographymanufactured by Hitachi, Ltd. wherein “Inertsil ODS-3 Column” (ex GLScience) is used), whereby 0.18 g of N,N′-di(n-hexanoyl)-L-cystinediamide was obtained.

Similarly, various N,N′-diacyl-L-cystine diamides were obtained. Theyare novel compounds not yet published. The measuring results of massspectra of these compounds are shown in Table 1.

TABLE 1 Mass Spectra (M + H) New Compounds Measured Calcd.N,N′-di(butyryl)-L-cystine diamide 379 379 N,N′-di(n-valeryl)-L-cystinediamide 407 407 N,N′-di(n-hexanoyl)-L-cystine diamide 435 435N,N′-di(octanoyl)-L-cystine diamide 491 491

SYNTHESIS EXAMPLE 2 Synthesis of Cystine Dialkyl Ester Derivatives

To 25 ml of acetonitrile were added successively 0.50 g of L-cystinedimethyl ester dihydrochloride, 0.55 g of n-pentanoic anhydride and 0.31g of triethylamine, followed by stirring overnight at room temperature.The reaction mixture was concentrated, and the crude crystals thusobtained were purified by high-performance liquid chromatography as inSynthesis Example 1, whereby 0.38 g of N,N′-di(n-valeryl)-L-cystinedimethyl ester was obtained.

Similarly, various N,N′-diacyl-L-cystine dialkyl esters andN,N′-diacyl-DL-homocystine dialkyl esters were obtained.

Next will be given Test Examples.

TEST EXAMPLE 1 Test on the Function of Inhibiting the Activation ofNF-κB Induced by Ultraviolet Rays

Each of the test compounds was added to a culture plate at aconcentration within an extent not causing a damage to the humanepidermal cells which had reached the confluent stage in the cultureplate. After 18 hours had elapsed, the culture medium was substituted bya phenol red-free medium. The cells were exposed to ultraviolet rays(UVB: 50 mJ/cm²) from an ultraviolet irradiator “Dermaray M-DMR-80” (exToshiba Medical Supply Co., Ltd.). After 4 to 5 hours had elapsed, thecells were collected, and the nucleoprotein was extracted therefrom in amanner known per se in the art. From the resulting nucleoprotein, theactivated NF-κB was detected in accordance with the gel shift assay. Theamount of the NF-κB was determined by measuring the radioactive value ofthe NF-κB band with the use of a bioimaging analyzer “BAS 2000” (ex FujiFilm Co., Ltd.).

The inhibition ratio of the activation of the NF-κB of the testcompounds was calculated from the below-described formula (1). Theresults of the test compounds of the present invention are shown belowin Table 2a, while those of the comparative compounds are shown below inTable 2b.

Inhibition ratio of NF-κB activation (%)

={1−(A ₁ −A ₃)/(A ₂ −A ₃)}×100  (1)

wherein, A1: radioactive value of the NF-κB upon addition of a testcompound

A2: radioactive value of NF-κB when a test compound is not added

A3: radioactive value of NF-κB when a test compound is not added and isnot exposed to ultraviolet rays.

TABLE 2a Addition Inhibition concentration ratio Test compounds (mM) (%)N,N′-di (n-butyryl)-L- 0.01 45 cystine diamide 0.1 11 N,N′-di(n-valeryl)-L- 0.01 8 cystine diamide 0.1 53 N,N′-di (n-hexanoyl)-L-0.01 24 cystine diamide 0.1 93 N,N′-di (n-octanoyl)-L- 0.01 66 cystinediamide 0.1 61 N,N′-diacetyl-L- 0.01 47 cystine dimethyl ester 0.1 86N,N′-diacetyl-L- 0.01 37 cystine diethyl ester 0.1 107 N,N′-diacetyl-L-0.01 19 cystine diisopropyl ester 0.1 48 N,N′-di (n-propionyl)-L- 0.0117 cystine dimethyl ester 0.1 54 N,N′-di (n-butyryl)-L- 0.01 52 cystinedimethyl ester 0.1 79 N,N′-di (n-valeryl)-L- 0.01 18 cystine dimethylester 0.1 64 N,N′-di (n-hexanoyl)-L- 0.01 43 cystine dimethyl ester 0.177 N,N′-di (n-heptanoyl)-L- 0.01 25 cystine dimethyl ester 0.1 103N,N′-di (n-octanoyl)-L- 0.01 33 cystine dimethyl ester 0.1 91 N,N′-di(n-decanoyl)-L- 0.01 56 cystine dimethyl ester 0.1 68 N,N′-dilauroyl-L-0.01 52 cystine dimethyl ester 0.1 59 N,N′-diacetyl-DL- 0.01 10homocystine dimethyl ester 0.1 46 L-cysteine ethyl ester 0.5 60 1 61 5Toxicity expressed N-acetyl-L- 0.01 28 cysteine methyl ester 0.1 95N-acetyl-L- 0.01 31 cysteine ethyl ester 0.1 74 N-acetyl-L- 0.01 21cystine isopropylester 0.1 82 N,S-diacetyl-L- 0.01 20 cystine methylester 0.1 31 L-cystine diethyl ester 0.1 50 0.5 >100 1 Toxicityexpressed N-lauroyl-L-cysteine 0.1 14 0.5 86 10 Toxicity expressedN-lauroyl-L- 0.01 36 cysteine methyl ester 0.1 43

TABLE 2b Addition Inhibition concentration ratio Test compounds (mM) (%)desferrioxamine 1 −83 5 −112 10 Toxicity expressed pyrrolidine 0.005 −2dithiocarbamate 0.01 9 0.05 Toxicity expressed N-acetyl-L-cysteine 10 2330 55 50 Toxicity expressed N,N′-diacetyl-L-cystine 10 48 30 67 50Toxicity expressed

As shown in Table 2b, known NF-κB activation inhibitors such asdesferrioxamine (ex. AIDS Reseasrch and Human Retroviruses, Vol. 11, pp.1049 to 1061, 1995) or pyrrolidines dithiocarbamate (ex. Immunology,Vol. 90, pp. 445-460, 1997) did not exhibit the NF-κB activationinhibiting function in this test, while as shown in Table 2a, anycompounds according to the present invention exhibited the suppressingor inhibiting function. In addition, the compounds according to thepresent invention exhibited their suppressing activity at aconcentration not greater than 0.5 mM, higher than ofN-acetyl-L-cysteine or N,N′-diacetyl-L-cystine (as shown in Table 2b)which exhibited their inhibiting function only at a concentration notless than 1 mM. From these results, it can be understood that thecompounds according to the present invention has high oxidative stresssuppressing or inhibiting function.

TEST EXAMPLE 2 Test on Suppressing Function of Wrinkles FormationInduced by Ultraviolet Rays (No. 1)

Hairless mice (SKH-1, female, 5-6 weeks old) were exposed to ultravioletrays (UVB) three times/week (Monday, Wednesday and Friday) for 5 weeks,each at 50 to 100 mJ/cm² by using the above-described “DermarayM-DMR-80” (ex Toshiba Medical Supply Co., Ltd.). The test compound(N,N′-diacetyl-L-cystine dimethyl ester) was dissolved in a mixedsolvent of propylene glycol, ethanol and water, and was applied to theback portion of each of the mice in an amount of 100 μl, 30 to 60minutes before exposure to ultraviolet rays, just after the completionof the exposure, and on the days free from exposure to ultraviolet rays(Sunday, Tuesday, Thursday and Saturday). From two weeks after theexposure had started, the wrinkles formed on the back portion of eachmouse were evaluated once a week based on the below-described standards,and they were indicated as scores. In addition, the function of theinventive compound for inhibiting wrinkle formation induced byultraviolet rays was judged based on the below-described judgingstandards. The results are shown below in Table 3.

Evaluation standards Score: 0 Formation of wrinkles is not recognized.Score: 1 Anisotropic formation of fine wrinkles is recognized. Score: 2Isotropic formation of fine wrinkles is recognized. Score: 3 Wrinkles ofScore 2 but having increased depth are recognized. Score: 4 Formation ofevident and deep wrinkles is recognized. Score: 5 Formation of evidentand deep wrinkles with flabbiness is recognized. Judging standardsJudgment: ⊚ The average score of the inventive product-applied group islower by at least 1.5 than that of the solvent- applied group. Judgment:◯ Lower by at least 1.0 but less than 1.5 in the same comparison.Judgment: Δ lower by at least 0.5 but less than 1.0 in the samecomparison. Judgment: X lower by less than 0.5 in the same comparison.

TABLE 3 Score and judgment Mouse 2nd 3rd 4th 5th Groups No. week weekweek week Solvent-applied group 1 3 3 3 3 2 3 4 4 4 3 3 4 4 5 4 3 4 4 55 1 4 4 5 6 2 2 4 4 7 3 4 5 5 Average 2.6 3.6 4.0 4.4 10%N,N′-diacetyl-L- 8 2 2 3 2 cystine dimethyl ester- 9 1 3 5 3 appliedgroup 10 1 1 5 4 11 0 2 2 2 12 1 2 3 2 13 3 2 3 3 14 1 2 4 3 Average 1.32.0 3.6 2.7 Judgment ◯ ⊚ Δ ◯

As shown in Table 3, N,N′-diacetyl-L-cystine dimethyl ester exhibitedeffects for retarding and alleviating the wrinkle formation induced byultraviolet rays, suggesting that the compounds of the present inventionare useful as an effective ingredient in a method for preventing,retarding, alleviating or treating a dermal change induced by anoxidative stress.

TEST EXAMPLE 3 Test on the Function of Inhibiting the AP-1 ActivationInduced by Ultraviolet Rays

In a similar manner to Test Example 1, a nucleoprotein was obtained.Then, the activated AP-1 was detected by the gel shift assay. Theradioactive value of the AP-1 band was measured as in Test Example 1,whereby the amount of the AP-1 was determined. The AP-1 activationinhibiting ratio of the test compounds was calculated by thebelow-described equation (2). The results of the test compoundsaccording to the present invention are shown below in Table 4a, whilethose of the comparative compounds are shown below in Table 4b.

AP-1 activation inhibiting ratio (%)

={1−(B ₁ −B ₃)/(B ₂ −B ₃)}×100  (2)

wherein, B₁: radioactive value of the AP-1 band upon addition of a testcompound.

B₂: radioactive value of the AP-1 band when a test compound is notadded.

B₃: radioactive value of the AP-1 band when a test compound is not addedand is not exposed to ultraviolet rays.

TABLE 4a Inhibiting ratio Test compounds (Concentration) (%)N,N′-diacetyl-L-cystine dimethyl ester (10 μM) 4 dl-α-tocopherol (10 μM)5 dl-α-tocopherol (100 μM) −1 dl-α-tocopherol (10 μM) + 102N,N′-diacetyl-L-cystine dimethyl ester (10 μM) L(+)ascorbic acid (0.1mM) 1 L(+)ascorbic acid (1 mM) 0 L(+)ascorbic acid (1 mM) + 54N,N′-diacetyl-L-cystine dimethyl ester (10 μM) N-acetyl-L-cysteine (0.1mM) 0 N-acetyl-L-cysteine (1 mM) −13 N-acetyl-L-cysteine (1 mM) + 53N,N′-diacetyl-L-cystine dimethyl ester (10 μM) glycyrrhetinic acid (10μM) 2 glycyrrhetinic acid (100 μM) −104 glycyrrhetinic acid (10 μM) + 85N,N′-diacetyl-L-cystine dimethyl ester (10 μM) glycyrrhizic acid (0.1mM) −3 glycyrrhizic acid (1 mM) −70 glycyrrhizic acid (0.1 mM) + 39N,N′-diacetyl-L-cystine dimethyl ester (10 μM)4-tert-butyl-4′-methoxybenzoylmethane (1 μM) −144-tert-butyl-4′-methoxybenzoylmethane (10 μM) 174-tert-butyl-4′-methoxybenzoylmethane (1 μM) + 31N,N′-diacetyl-L-cystine dimethyl ester (10 μM) 2-ethylhexylp-methoxycinnamate (10 μM) −20 2-ethylhexyl p-methoxycinnamate (100 μM)11 2-ethylhexyl p-methoxycinnamate (10 μM) + 103

TABLE 4b Inhibiting ratio Test compounds (Concentration) (%) astaxantin(1 μM) −54 astaxantin (10 μM) 0 astaxantin (100 μM) Toxicity expressedastaxantin (10 μM) + −16 N,N′-diacetyl-L-cystine dimethyl ester (10 μM)

As shown in Tables 4a and 4b, the above-described Components (A) and (B)when combined, exhibited a marked inhibiting function. The inhibitingfunction in such combination exceeded that of each of Components (A) and(B). This fact suggests that the oxidative stress activation can beinhibited or supressed more by synergism of the effects of Components(A) and (B).

TEST EXAMPLE 4 Test on Inhibiting Function of Wrinkles Formation inducedby Ultraviolet Rays (No. 2)

Function of suppressing ultraviolet ray-induced wrinkles formation bythe synergistic effects when Components (A) and (B) were used incombination, was judged in a similar manner to Test Example 2. Fifteento twenty mice were divided into 4 groups, that is, a 1st group to whicha mixed solvent of propylene glycol, ethanol and water was to beapplied, a 2nd group to which a solution of only Component (A) dissolvedin the above-described solvent was to be applied, a 3rd group to which asolution of only Component (B) dissolved in the above-described solventwas to be applied, and a 4th group to which a solution of bothComponents (A) and (B) dissolved in the above-described solvent was tobe applied. An average score of each group was determined. The resultsare shown below in Table 5.

TABLE 5 Score 2nd 3rd 4th 5th Text compounds (Concentration) week weekweek week Solvent 3.0 3.7 4.7 3.7 N,N′-diacetyl-L-cystine dimethyl 1.52.5 3.0 4.0 ester (10%) dl-α-tocopherol (5%) 2.0 3.0 2.5 3.5dl-α-tocopherol (5%) + 2.0 3.0 2.0 2.7 N,N′-diacetyl-L-cystine dimethylester (10%) Solvent 2.3 4.0 4.3 4.7 N,N′-diacetyl-L-cystine dimethyl 1.01.0 5.0 4.0 ester (10%) L(+)-ascorbic acid (5%) 1.0 2.0 4.0 4.0L(+)-ascorbic acid (5%) + 1.0 1.3 2.3 3.3 N,N′-diacetyl-L-cystinedimethyl ester (10%) Solvent 3.0 3.7 4.7 3.7 N,N′-diacetyl-L-cystinedimethyl 1.5 2.5 3.0 4.0 ester (10%) Salicylic acid (5%) 2.0 1.5 1.5 2.5Salicylic acid (5%) + 1.0 1.0 1.7 2.7 N,N′-diacetyl-L-cystine dimethylester (10%) Solvent 1.3 1.7 3.3 3.0 N,N′-diacetyl-L-cystine dimethyl 0.52.0 2.5 2.0 ester (10%) 2-ethylhexyl p-methoxycinnmate 0.0 0.5 1.5 0.5(3%) 2-ethylhexyl p-methoxycinnmate 0.0 0.7 0.3 0.0 (3%) +N,N′-diacetyl-L-cystine dimethyl ester (10%)

As shown in Table 5, the inhibiting function of the Components (A) and(B) when used in combination, exceeded that of Component (A) or (B) whenused each singly. For example, N,N′-diacetyl-L-cystine dimethyl esterwhen used in combination with dl-α-tocopherol, ascorbic acid, or 2-ethylp-methoxycinnamate, gave synergistic effects from four weeks after theultraviolet exposure had started. And, N,N′-diacetyl-L-cystine dimethylester when used in combination with salicylic acid gave synergisticeffects from Week 2 or Week 3. According to the present invention, adermal change caused by an oxidative stress can be suppressed bysynergism of Components (A) and (B) when used in combination.

Finally, Formulation Examples 1-13 of various preparations will begiven, using an oxidative stress inhibitor of the present invention.

Formulation Example 1: Tablet N-acetyl-L-cysteine laurylamide 5%N,N′-dilauroyl-L-cystine dimethyl ester 5 Lactose 50 Starch 20Carboxymethyl cellulose 19 Magnesium stearate 1 Formulation Example 2:Injection N-lauroyl-L-cysteine amide 0.1% Glucose 2.0 Distilled waterfor injection Balance Formulation Example 3: Ointment L-Cysteine laurylamide 0.5% N-lauroyl-L-cysteine 1.0 Urea 20.0 White vaseline 15.0 Lightliquid paraffin 6.0 Cetanol 3.0 Stearyl alcohol 3.0 Glycerylmonostearate 5.0 Perfume q.s. Antiseptic q.s. Buffer 1.0 Purified waterBalance Formulation Example 4: Cream N,N′-diacetyl-L-cystine dimethylester 1.0% Magnesium ascorbate phosphate 1.0 Stearic acid 2.0Polyoxyethylene (25) cetyl ether 3.0 Glyceryl monostearate 2.0 Octyldodecanol 10.0 Cetanol 6.0 Reduced lanolin 4.0 Squalane 9.0 1,3-Butyleneglycol 6.0 Polyethylene glycol (1500) 4.0 Antiseptic q.s. Perfume q.s.Antioxidant q.s. Purified water Balance Formulation Example 5: CreamN,N′-diacetyl-L-cystine diisopropyl ester 1.0%N,N′-di(n-butyryl)-L-cystine amide 1.0 Glyceryl monostearate 2.0Polyoxyethylene (20) sorbitan monolaurate 1.0 Paraffin 5.0 Bees wax 10.0Vaseline 15.0 Liquid paraffin 41.0 Boric acid 0.2 1,3-Butylene glycol4.0 Antiseptic q.s. Perfume q.s. Purified water Balance FormulationExample 6: Milky lotion L-cysteine ethyl ester 2.0% N-acetyl-L-cysteineethyl ester 1.0 Retinol 0.1 Bees wax 0.5 Vaseline 2.0 Glycerylmonostearate 1.0 Polyethylene glycol monooleate 1.0 Methyl polysiloxane2.0 Cetanol 1.0 Squalane 6.0 Corboxyvinyl polymer 0.5 1,3-Butyleneglycol 4.0 Ethanol 5.0 Antiseptic q.s. Perfume q.s. Purified waterBalance Formulation Example 7: Milky lotionN,N′-di(n-hexanoyl)-L-cystine ester diamide 1.5% N-lauroyl-L-cysteinemethyl ester 0.5 Sodium salicylate 0.1 Sorbitan sesquioleate 1.6Polyoxyethylene oleyl ether 2.4 Stearyl alcohol 0.5 Hardened palm oil3.0 Liquid paraffin 35.0 Dipropylene glycol 6.0 Polyethylene glycol(400) 4.0 Corboxyvinyl polymer (aqueous 1% solution) 15.0 Potassiumhydroxide 0.1 Antiseptic q.s. Perfume q.s. Purified water BalanceFormulation Example 8: Gel N-monolauroyl-L-cystine 0.05% Liquid paraffin12.0 Glyceryl tri(2-ethylhexanoate) 50.0 Sorbitol 10.0 Polyethyleneglycol (400) 5.0 Acylmethyl taurine 5.0 Polyoxyethylene (20) isocetylether 10.0 Perfume q.s. Antiseptic q.s. Purified water BalanceFormulation Example 9: Vitalizing lotion N,N′-diacetyl-L-cystinedimethyl ester 0.5% Dipropylene glycol 5.0 Polyethylene glycol (400) 5.0Ethanol 10.0 Carboxyvinyl polymer 0.5 Sodium alginate 0.5 Potassiumhydroxide 0.2 Polyoxyethylene (20) sorbitan monostearate 1.0 Sorbitanmonooleate 0.5 Oleyl alcohol 0.5 Placenta extract 0.2 dl-α-tocopherolacetate 0.2 Perfume q.s. Antiseptic q.s. Discoloration inhibitor q.s.Purified water Balance Formulation Example 10: Vitalizing lotionN,N′-diacetyl-L-cystine dimethyl ester 1.5% 2-Ethylhexylp-methoxycinnamate 4.0 3,3′-(1,4-phenylenedimethylidyne) bis (7,7- 4.0dimethyl-2-oxo-bicyclo[2.2.1]heptane-1- methanesulfonic acid)Polyoxyethylene cetyl ether 2.0 Glyceryl monostearate 2.0 Stearic acid3.0 Cetanol 1.0 Lanolin 3.0 Liquid paraffin 5.0 2-Ethylhexyl stearate3.0 1,3-Butylene glycol 6.0 Perfume q.s. Antiseptic q.s. Purified waterBalance Formulation Example 11: Pack L-cystine diethyl ester 3.0%Polyvinyl alcohol 15.0 Carboxymethyl cellulose 5.0 1,3-Butylene glycol5.0 Ethanol 12.0 Polyoxyethylene (20) oleyl ether 0.5 Perfume q.s.Antiseptic q.s. Buffer q.s. Purified water Balance Formulation Example12: Foundation N-(2-hydroxylauryl)-L-cysteine 4.0%4-tert-butyl-4′-methoxybenzoylmethane 1.0 Liquid paraffin 10.0Polyoxyethylene (20) sorbitan Monooleate 3.5 Propylene glycol 3.0Titanium oxide 9.0 Kaolin 24.0 Talc 42.0 Coloring pigment 3.0 Perfumeq.s. Antiseptic q.s. Antioxidant q.s. Formulation Example 13: Face washN,S-diacetyl-L-cysteine methyl ester 1.0% Stearyl glycyrrhetinate 0.1N-laurylglutamic acid triethanolamine salt 25.0 Triethanolamine laurate5.0 Polyoxyethylene (4) polyoxypropylene (11) 5.0 butyl ether Licoriceextract 1.0 Ethanol 3.0 Perfume q.s. Antiseptic q.s. Purified waterBalance

Industrial Applicability

The oxidative stress activation inhibitor or the inhibiting method ofthe present invention exhibits excellent function, performance orcapacity for suppressing or inhibiting the oxidative stress activation.The cosmetic composition or dermatologic preparation for external usecontaining the oxidative stress inhibitor of the present invention, whenapplied to the skin, remains on the skin effectively and can not beremoved easily, and at the same time provides good feeling upon use.

What is claimed is:
 1. A cysteine or cystine compound represented byformula (I) or a salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-heptanoyl,nonanoyl, isononanoyl, undecanoyl, tridecanoyl, isotridecanoyl, oleoyl,and docosanoyl; an alkyl group having 1-22 carbon atoms; a hydroxyalkylgroup having 1-22 carbon atoms; or a 3-alkoxy-2-hydroxypropyl groupwhose alkoxyl group has 1-22 carbon atoms; each E represents,independently, a hydrogen atom or an alkyl group having 1-6 carbonatoms; g stands for an integer of 0 to 5; R² represents a hydrogen atom,an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxylgroup has 1-22 carbon atoms, with the proviso that when R¹ represents ahydrogen atom or an acyl group having 2-3 carbon atoms, R² represents analkyl group having 6-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; R³ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms, a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atomsor a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 2. An oxidative stress inhibitor composition, which comprises, asan effective ingredient, at least one cysteine or cystine compound offormula (I) or salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents an aminocarbonyl group, an acyl group having 2-22carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms or a group represented by formula(1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 3. A method for preventing and/or treating an oxidativestress-induced disease, which comprises treating a subject in needthereof with an effective amount of an oxidative stress inhibitorcomposition according to claim
 1. 4. The method of claim 3, wherein saidoxidative stress-induced disease is an ultraviolet rays-induced disease.5. A cosmetic composition or a dermatologic preparation for external usewhich comprises: Component (A) which is at least one cysteine or cystinecompound represented by formula (I) or a salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents an aminocarbonyl group, an acyl group having 2-22carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms or a group represented by formula(1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; and Component (B) which is at least one ingredient selected fromthe group consisting of antioxidants, anti-inflammatory drugs, andultraviolet absorbors.
 6. The cosmetic composition or dermatologicpreparation for external use of claim 5, wherein said anti-oxidant isselected from the group consisting of vitamin C, vitamin E, derivativesthereof, and salts thereof, and N-acetyl cysteine.
 7. The cosmeticcomposition or dermatologic preparation for external use of claim 5,wherein said anti-inflammatory drug is selected from the groupconsisting of glycyrrhetinic acid, glycyrrhizic acid, or salicylic acid,derivatives thereof, and salts thereof.
 8. The cosmetic composition ordermatologic preparation for external use of claim 5, wherein saidultraviolet absorber is selected from the group consisting ofbenzophenone derivatives, p-aminobenzoic acid and derivatives thereof,methoxycinnamic acid derivatives, salicylic acid derivatives, urocanicacid and derivatives thereof, 4-tert-butyl-4′-methoxy dibenzoylmethane,and 2-(2′-hydroxy-5′-methylphenyl)benzotriazole.
 9. The cosmeticcomposition or dermatologic preparation for external use of claim 5,wherein said at least one cysteine or cystine compound represented byformula (I) or salt thereof is present in an amount of 0.01 to 10 wt. %,based on the weight of said cosmetic composition or dermatologicpreparation for external use.
 10. The cosmetic composition ordermatologic preparation for external use of claim 5, wherein said atleast one cysteine or cystine compound represented by formula (I) orsalt thereof is present in an amount of 0.1 to 5 wt. %, based on theweight of said cosmetic composition or dermatologic preparation forexternal use.
 11. The cosmetic composition or dermatologic preparationfor external use of claim 5, wherein said at least one cysteine orcystine compound represented by formula (I) or salt thereof is presentin an amount of 0.01 to 50 wt. %, based on the weight of said cosmeticcomposition or dermatologic preparation for external use.
 12. Thecosmetic composition or dermatologic preparation for external use ofclaim 5, wherein said at least one cysteine or cystine compoundrepresented by formula (I) or salt thereof is present in an amount of0.1 to 20 wt. %, based on the weight of said cosmetic composition ordermatologic preparation for external use.
 13. A method for preventing,retarding, alleviating or treating a skin change due to aging or anundesirable aesthetic skin change, both caused or promoted by anoxidative stress, which method comprises applying onto the skin acosmetic composition or a dermatologic preparation for external usewhich comprises: Component (A) which is at least one cysteine or cystinecompound represented by formula (I) or a salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents a hydrogen atom, an aminocarbonyl group, an acylgroup having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms,a hydroxyalkyl group having 1-22 carbon atoms, a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atomsor a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; and Component (B) which is at least one ingredient selected fromthe group consisting of antioxidants, anti-inflammatory drugs, andultraviolet absorbors.
 14. The method of claim 13, wherein said skinchange due to aging or an undesirable aesthetic skin change, both causedor promoted by an oxidative stress, is induced by sunlight orultraviolet rays therefrom.
 15. The method of claim 13, wherein saidanti-oxidant is selected from the group consisting of vitamin C, vitaminE, derivatives thereof, and salts thereof, and N-acetyl cysteine. 16.The method of claim 13, wherein said anti-inflammatory drug is selectedfrom the group consisting of glycyrrhetinic acid, glycyrrhizic acid, orsalicylic acid, derivatives thereof, and salts thereof.
 17. The methodof claim 13, wherein said ultraviolet absorber is selected from thegroup consisting of benzophenone derivatives, p-aminobenzoic acid andderivatives thereof, methoxycinnamic acid derivatives, salicylic acidderivatives, urocanic acid and derivatives thereof,4-tert-butyl-4′-methoxy dibenzoylmethane, and2-(2′-hydroxy-5′-methylphenyl)benzotriazole.
 18. The method of claim 13,wherein said at least one cysteine or cystine compound represented byformula (I) or salt thereof is present in an amount of 0.01 to 10 wt. %,based on the weight of said cosmetic composition or dermatologicpreparation for external use.
 19. The method of claim 13, wherein saidat least one cysteine or cystine compound represented by formula (I) orsalt thereof is present in an amount of 0.01 to 50 wt. %, based on theweight of said cosmetic composition or dermatologic preparation forexternal use.
 20. The method of claim 13, wherein said at least onecysteine or cystine compound represented by formula (I) or salt thereofis applied to the skin in an amount of 0.003 μg/cm² to 200 mg/cm².
 21. Amethod for treating a skin change due to oxidative stress, whichcomprises treating a subject in need thereof with an effective amount ofan oxidative stress inhibitor composition according to claim
 2. 22. Themethod of claim 21, wherein said skin change is due to an ultravioletrays-induced disease.
 23. A cysteine or cystine compound represented byformula (I) or a salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-heptanoyl,nonanoyl, isononanoyl, undecanoyl, tridecanoyl, isotridecanoyl, anddocosanoyl; an alkyl group having 1-22 carbon atoms; a hydroxyalkylgroup having 1-22 carbon atoms; or a 3-alkoxy-2-hydroxypropyl groupwhose alkoxyl group has 1-22 carbon atoms; each E represents,independently, a hydrogen atom or an alkyl group having 1-6 carbonatoms; g stands for an integer of 0 to 5; R² represents a hydrogen atom,an alkyl group having 1-22 carbon atoms, a hydroxyalkyl group having1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxylgroup has 1-22 carbon atoms, with the proviso that when R¹ represents ahydrogen atom or an acyl group having 2-3 carbon atoms, R² represents analkyl group having 6-22 carbon atoms, a hydroxyalkyl group having 1-22carbon atoms or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has1-22 carbon atoms; R³ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms, a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atomsor a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 24. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom; an alkyl group selected from the groupconsisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-amyl, sec-amyl, tert-amyl, isoamyl, n-hexyl,cyclohexyl, n-heptyl, n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl,isodecyl, undecyl, lauryl, tridecyl, isotridecyl, myristyl, stearyl,isostearyl, oleyl, and behenyl; a hydroxyalkyl group having 1-22 carbonatoms; or a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22carbon atoms, with the proviso that when R¹ represents a hydrogen atomor an acyl group having 2-3 carbon atoms, R² represents an alkyl grouphaving 6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atomsor a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents an aminocarbonyl group, an acyl group having 2-22carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms or a group represented by formula(1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 25. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-hexanoyl,cyclohexanoyl, n-heptanoyl, n-octanoyl, 2-ethylhexanoyl, nonanoyl,isononanoyl, decanoyl, isodecanoyl, undecanoyl, lauroyl, tridecanoyl,isotridecanoyl, myristoyl, palmitoyl, isopalmitoyl, stearoyl,isostearoyl, oleoyl, and docosanoyl; an alkyl group having 1-22 carbonatoms; a hydroxyalkyl group having 1-22 carbon atoms; or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents an aminocarbonyl group, an acyl group having 2-22carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms or a group represented by formula(1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 26. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-hexanoyl,cyclohexanoyl, n-heptanoyl, n-octanoyl, 2-ethylhexanoyl, nonanoyl,isononanoyl, decanoyl, isodecanoyl, undecanoyl, lauroyl, tridecanoyl,isotridecanoyl, myristoyl, and docosanoyl; an alkyl group having 1-22carbon atoms; a hydroxyalkyl group having 1-22 carbon atoms; or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents an aminocarbonyl group, an acyl group having 2-22carbon atoms, an alkyl group having 1-22 carbon atoms, a hydroxyalkylgroup having 1-22 carbon atoms, a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms or a group represented by formula(1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 27. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-hexanoyl,cyclohexanoyl, n-heptanoyl, n-octanoyl, 2-ethylhexanoyl, nonanoyl,isononanoyl, decanoyl, isodecanoyl, undecanoyl, lauroyl, tridecanoyl,isotridecanoyl, myristoyl, palmitoyl, isopalmitoyl, stearoyl,isostearoyl, oleoyl, and docosanoyl; an alkyl group having 1-22 carbonatoms; a hydroxyalkyl group having 1-22 carbon atoms; or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents an alkyl group having 1-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms, with the proviso that when R¹represents a hydrogen atom or an acyl group having 2-3 carbon atoms, R²represents an alkyl group having 6-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms; R³ represents a hydrogen atom, anaminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkylgroup having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbonatoms, a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22carbon atoms or a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 28. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom; an aminocarbonylgroup; an acyl group selected from the group consisting of acetyl,propionyl, isopropionyl, n-butyryl, isobutyryl, sec-butyryl,tert-butyryl, n-valeryl, sec-valeryl, pivaloyl, isovaleryl, n-hexanoyl,cyclohexanoyl, n-heptanoyl, n-octanoyl, 2-ethylhexanoyl, nonanoyl,isononanoyl, decanoyl, isodecanoyl, undecanoyl, lauroyl, tridecanoyl,isotridecanoyl, myristoyl, and docosanoyl; an alkyl group having 1-22carbon atoms; a hydroxyalkyl group having 1-22 carbon atoms; or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents an alkyl group having 1-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms, with the proviso that when R¹represents a hydrogen atom or an acyl group having 2-3 carbon atoms, R²represents an alkyl group having 6-22 carbon atoms, a hydroxyalkyl grouphaving 1-22 carbon atoms or a 3-alkoxy-2-hydroxypropyl group whosealkoxyl group has 1-22 carbon atoms; R³ represents a hydrogen atom, anaminocarbonyl group, an acyl group having 2-22 carbon atoms, an alkylgroup having 1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbonatoms, a 3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22carbon atoms or a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.
 29. A cysteine or cystine compound represented by formula (I) ora salt thereof:

wherein in formula (I): R¹ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each E represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; g stands for an integer of 0 to 5; R²represents an alkyl group selected from the group consisting of methyl,ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,n-amyl, sec-amyl, tert-amyl, isoamyl, n-hexyl, cyclohexyl, n-heptyl,n-octyl, 2-ethylhexyl, nonyl, isononyl, decyl, isodecyl, undecyl,lauryl, tridecyl, isotridecyl, myristyl, stearyl, isostearyl, oleyl, andbehenyl; a hydroxyalkyl group having 1-22 carbon atoms; or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R¹ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R² represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; R³ represents a hydrogen atom, an aminocarbonyl group, an acylgroup having 2-22 carbon atoms, an alkyl group having 1-22 carbon atoms,a hydroxyalkyl group having 1-22 carbon atoms, a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbon atomsor a group represented by formula (1):

wherein in formula (1): R⁴ represents a hydrogen atom, an aminocarbonylgroup, an acyl group having 2-22 carbon atoms, an alkyl group having1-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms; each F represents, independently, a hydrogen atom or an alkylgroup having 1-6 carbon atoms; h stands for an integer of 0 to 5; R⁵represents a hydrogen atom, an alkyl group having 1-22 carbon atoms, ahydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms, with the proviso that when R⁴ represents a hydrogen atom or anacyl group having 2-3 carbon atoms, R⁵ represents an alkyl group having6-22 carbon atoms, a hydroxyalkyl group having 1-22 carbon atoms or a3-alkoxy-2-hydroxypropyl group whose alkoxyl group has 1-22 carbonatoms.